The present invention relates to therapeutic ultrasound methods and catheter systems.
Therapeutic ultrasound systems have proven effective in enhancing transdermal drug delivery, ablating pathological tissue and non-invasively breaking up concretions within the body. To achieve maximum therapeutic benefits, it is desirable to deliver ultrasound energy as directly as possible to the treatment site. Unfortunately, such treatment site may be within a body lumen, such as a vascular site, where numerous problems exist in attempting to direct therapeutic ultrasound. For example, it is difficult to design a sufficiently flexible device to deliver ultrasound energy along the curved tortuous path of the body lumen, especially for narrow diameter body lumens.
Moreover, to deliver maximum therapeutic benefits along a body lumen treatment region, it is desirable to direct a uniform dosage of ultrasonic energy along the length of the lumen with the dosage of the ultrasound energy varying only minimally along the length of the lumen. Delivering a uniform dose of therapeutic ultrasound energy along the length of the body lumen is especially desirable when concurrently using stents in the lumen. When using stents, overstretching of the vascular wall during stent insertion can cause wall tearing and denudation of endothelial cells which can result in an over proliferative healing response. Therapeutic ultrasound following wall injury reduces the formation of obstructive neointimal hyperplasia. A uniform dose of therapeutic ultrasound would reduce the formation of such hyperplasia along the length of the lumen, and in particular along the length of the stent.
It has proven especially difficult to generate such a uniform ultrasonic field along the length of a body lumen due in part to the typically curved path of the lumen and the dimensions of the ultrasound transducers.
Ultrasound systems which are effective in enhancing transdermal drug delivery operate at frequencies around 1 MHz, and tend to be quite large due to the large surface area that it is necessary to affect. Such large transducers are not suitably dimensioned for catheter placement into the small lumens of a patient""s body. Moreover, smaller transducers which operate at higher frequencies, (such as 10 to 50 MHZ), are not adapted to generate sufficient energy to enhance in vivo drug delivery, or to cause other therapeutic effect, such as reducing the formation of obstructive neointimal hyperplasia after stent implantation. Instead, such small high frequency transducers are limited to diagnostic applications.
For catheter based systems, achieving the optimal size of the ultrasound transducer is problematic since a small catheter mounted transducer is only able to deliver a small amount of ultrasound energy to the patient. Conversely, a larger device, (which would deliver more therapeutic energy), requires a larger transducer which would unfortunately limit the flexibility of the catheter, thus making access difficult in narrow vascular regions.
In addition, a small catheter mounted transducer is adapted to deliver ultrasound only to the region of the lumen immediately adjacent the transducer, for example at the distal tip of the catheter. An additional problem when using a plurality of ultrasound transducers spaced apart along the length of the catheter is the non-uniformity of ultrasound dose delivered since maximum ultrasound will be delivered adjacent the transducers and minimal ultrasound will be delivered at locations equally spaced between adjacent transducers. Accordingly, it is especially difficult to deliver a uniform dose of ultrasound energy along the length of the body lumen.
U.S. Pat. No. 5,197,946 and published PCT Applications WO 96/27341 and WO 98/18391 to Tachibana disclose catheters having an ultrasound transducer at their distal end. Published PCT Application WO 98/48711 to Tachibana discloses a flexible catheter system directed to providing ultrasound for treating long lesions by providing a catheter having a number of separate ultrasound transducers spaced apart therealong. Published PCT Application WO 96/29935 to Crowley discloses a catheter system for tissue ablation having a plurality of annular shaped ultrasonic transducers spaced apart along the length of the catheter.
The present invention provides methods and systems for treating a target region in a body lumen by delivering a uniform dose of ultrasonic energy from an interior of the lumen radially outward along a portion of the length of the lumen. As will be explained herein, a xe2x80x9cuniformxe2x80x9d dosage of ultrasound energy corresponds to ultrasound energy producing a uniform biological effect around the circumference of the body lumen. Such uniform biological effects can be generated by mechanical effects related to cavitation, thermal bio-effects related to the absorption of ultrasound energy, radiation pressure forces arising from the absorption and reflection of ultrasound causing tension in the lumen to be equal around its circumference.
In a preferred aspect of the invention, the uniform dosage of ultrasonic energy received at any one point along the length of the lumen varies by no more xc2x16 decibels. Also in a preferred aspect of the invention, the uniform dosage of ultrasonic energy will be applied over a length greater than the diameter of the body lumen at the treatment site, usually being at least 0.8 cm of the lumen often being at least 1 cm, and sometimes being 2 cm, 3 cm, or longer.
In various aspects of the present invention, one or more ultrasound transducers are used to generate the uniform dose of ultrasound energy.
When using a single ultrasound transducer, the transducer may have an isotropic radiation pattern and be drawn axially through the lumen at a controlled velocity. Alternatively, when using a single non-isotropic ultrasound transducer, the transducer may be drawn axially through the lumen at a controlled velocity, while simultaneously being rotated about the central axis of the catheter at a controlled angular velocity.
When using a plurality of axially spaced apart isotropic transducers, the transducers may be drawn axially through the lumen at a controlled velocity. Alternatively, by dimensioning the axially spaced apart transducers such that they can be placed at a separation distance less than or equal to the diameter of the catheter, a generally uniform emission along the length of the body lumen can be generated without having to axially draw the transducers through the lumen.
When using a plurality of axially spaced apart non-isotropic transducers, the transducers may either be drawn axially through the lumen at a controlled velocity, rotated about the central axis of the catheter at a controlled angular velocity, or some combination thereof.
Preferred shapes for isotropic transducers include cylindrical or annular transducers having their central axes disposed parallel to the central axis of the catheter. A preferred shape for a non-isotropic transducer is a rectangular bar shaped transducer. Other non-isotropic shapes are also possible including cubic or octagonal shapes, parallel bar shapes or composite structures.
Preferred dimensions of the cylindrical, annular, rectangular or cubic transducers as set forth herein will cause the transducers to operate at resonance, thereby increasing the net therapeutic effect to the body lumen by providing maximum ultrasound energy.
When using a plurality of axially spaced apart transducers, the transducers can be operated in phase so as to cause tissue displacements in directions normal to a central axis of the lumen. Alternatively, the plurality of spaced apart transducers can be operated such that successive transducers are 180xc2x0 out of phase with one another such that ultrasound energy causing tissue shear displacement along the length of the lumen is produced.
Specifically, when using a plurality of either rectangular bar shaped or cylindrical transducers, (with the transducers being positioned with their electroded surfaces either parallel to, or perpendicular to, the catheter central axis), the polarities of respective transducers can be alternated such that as a first transducer expands in the axial direction, adjacent transducers positioned on either side will simultaneously contract in the axial direction. The axial expansion of the first transducer will create a radial contraction, thereby creating a negative acoustic emission in the radial direction. Simultaneously, the adjacent transducers on either side of the first transducer will contract axially and expand radially, thereby creating a positive acoustic emission in the radial direction. As such, successive transducers will generate alternating negative and positive radial emissions along the length of the catheter. Therefore, a radial acoustic emission field will be generated about the catheter which causes tissue shear displacement along the length of the lumen. An advantage of such a longitudinal shear emission field is that maximal effects will appear close to the catheter surface, (due to the fact that the alternating positive and negative pressure fields would tend to cancel one another out at progressively greater distances from the catheter surface). An additional advantage of this arrangement is that it limits the propagation distance of strong acoustic fields.
Alternatively, should successive transducers be aligned with polarities in the same direction, such that they operate together in phase, each of the successive axially spaced apart transducers will simultaneously emit either a positive or a negative acoustic emission in a radially direction. Therefore, an acoustic field having a generally even strength will be generated along the length of the catheter to cause tissue displacement in radial directions normal to a central axis of the lumen. Using this arrangement, however, it may be preferable to position acoustic insulators between adjacent transducers so as to reduce vibrational interference in the axial direction. The drop in acoustic output in the gaps between individual transducers will preferably be less than or equal to the limits set forth above.
In another aspect of the invention, when using non-isotropic rectangular bar shaped transducers, two or three of the four sides which are disposed parallel to the central axis of the catheter can be acoustically insulated (for example, with an air gap or other acoustic reflective material) such that ultrasound energy emission therefrom is blocked. By blocking ultrasound emission from two or three sides of the rectangular bar shaped transducer, ultrasound energy can be concentrated in one, or alternatively two, unblocked surfaces, thereby emitting ultrasound in directions normal to the central axis of the catheter, thereby increasing the dosage of ultrasound received by the body lumen. Rotation, and/or translation of the non-isotropic rectangular bar shaped ultrasound transducers at controlled velocities through the body lumen provides a uniform dose of ultrasound energy along the length of the body lumen.
By translating and/or rotating the present multi-transducer ultrasonic catheter systems, ultrasound energy can be evenly applied in a uniform dose along a portion of the body lumen in conjunction with the delivery of therapeutic agents along the body lumen.
As will be explained, an additional advantage of employing a plurality of spaced apart transducers is that, when axially translating the catheter to provide a uniform dose of ultrasound, it is only necessary to translate the catheter a distance equal to one half the spacing distance between adjacent transducers.
When employing a plurality of spaced apart ultrasound transducers, the present catheter systems deliver a larger amount of therapeutic ultrasound energy to the patient than could be achieved with a single small transducer. Using a number of small spaced apart ultrasound transducers, the present ultrasonic catheter systems are highly flexible and are thus able to access narrow body lumens. Advantageous applications of the present systems include administering ultrasonic energy for clot lysis, for drug delivery, to augment gene therapy as described in detail in copending application Ser. No. 09/223,231, now U.S. Pat. No. 6,372,498, the full disclosure of which is incorporated herein by reference), to prevent obstructive neointimal hyperplasia, (as described in detail in copending application Ser. No. 09/223,230, now U.S. Pat. No. 6,210,393, the full disclosure of which is incorporated herein by reference), and/or to inhibit proliferation of smooth muscle cells.
The catheter bodies of the present catheter systems will preferably contain at least two lumens, one for passing electrical leads to the transducer elements and one for positioning a guidewire therethrough. Additional lumens are added in various aspects of the present invention for the delivery of drugs, the inflation of balloons, and/or the evacuation of fluids from the vascular channel, as will be explained.
When using rectangular bar or cylindrical shaped transducers, the individual ultrasound transducers will preferably comprise single crystal piezoelectric materials, polycrystalline piezoelectric ceramic materials, electrostrictive or magnetostrictive materials. In a preferred aspect of the invention, the transducers are operated at a frequency in the range of 100 KHz to 5.0 MHZ.
When using a plurality of axially spaced apart non-isotropic rectangular bar shaped transducers, ultrasound energy will be emitted more strongly in certain radial directions perpendicular to the flat surfaces of the transducers which are parallel to the central axis of the catheter. To achieve a uniform dose of therapeutic ultrasound energy around and along the length of the body lumen, systems are provided to rotate the catheter about its central axis at a controlled angular velocity and to axially translate the catheter along its central axis at a controlled velocity.
In a preferred aspect, when using a plurality of axially spaced apart non-isotropic rectangular bar shaped transducers, the successive transducers can be positioned so as to be rotated about the longitudinal catheter axis with respect to one another. As such, an extended catheter which emits ultrasound energy in a number of different radial directions along its length is produced. By axially displacing the catheter through a body lumen at a controlled velocity, (without rotating the catheter about its central axis), a uniform dose of therapeutic ultrasound energy can also be directed along the length of the body lumen.
Alternatively, however, by rotating such a catheter at a controlled angular velocity, therapeutic ultrasound energy can also be directed radially around the circumference of the body lumen when the successive ultrasound transducers are spaced sufficiently close together. In such a case, rotation of the catheter at a controlled radial velocity about its central axis will provide a uniform dose of therapeutic ultrasound energy, without the need for axially displacing the catheter along the length of the body lumen.
In various aspects of the invention, the non-isotropic rectangular bar shaped transducers are positioned such that their electroded surfaces are parallel to the central longitudinal axis of the catheter. An advantage of positioning the electroded surfaces parallel to the central axis of the catheter is that a more non-isotropic emission pattern is generated. Specifically, in the case of rectangular bar transducers having electroded surfaces disposed parallel to the longitudinal axis of the catheter, a xe2x80x9ccloverleafxe2x80x9d non-isotropic acoustic emission field will be generated which is strongest in the four directions perpendicular to the four transducer faces which are disposed parallel to the longitudinal axis of the catheter. There will be nulls in the acoustic emission field in the four diagonal directions which dissect the perpendicular directions. Such a cloverleaf acoustic field will be generated due to the fact that displacements with respect to non-electroded surfaces will be 180xc2x0 out of phase with respect to the displacement of the electroded surfaces. Strong emissions will emanate from the four orthogonal tranducer faces while the vibrations will cancel on the diagonals between adjacent transducer faces. As such, a stronger amount of ultrasound energy, (corresponding to the xe2x80x9cleavesxe2x80x9d of the cloverleaf can be directed in preferred directions towards the body lumen. Translation and rotation of the transducers provides a uniform dose of ultrasound along the length of the body lumen.
In other preferred aspects, one or more rectangular bar transducers are positioned such that their electroded surfaces are instead perpendicular to the longitudinal axis of the catheter. An advantage of positioning electroded surfaces perpendicular to the longitudinal axis is that a greater emission symmetry around the body of the catheter will be generated, yielding a generally more isotropic dose of the ultrasound energy to be received by the body lumen. Translation and rotation of the transducers provides a uniform dose of ultrasound along the length of the body lumen.
When using a plurality of cylindrical shaped isotropic ultrasound transducers, the longitudinal axis of each cylindrical transducer and the longitudinal axis of the catheter are parallel and generally co-linear.
Electrodes are attached to opposite surfaces of each cylindrical shaped transducer. The electroded surfaces are disposed either parallel to, or perpendicular to, the central longitudinal axis of the catheter. Specifically, the flat ends of the cylinder, (perpendicular to the catheter central axis), may be used as the opposite electroded surfaces. Alternatively, a central bore can be cut through each of the cylindrical transducers with the inner and outer curved surfaces, (parallel to the central axis), serving as the electroded surfaces.
When using one or more cylindrical shaped transducers with the opposite electroded surfaces being the flat ends of the cylinder or the curved inner and outer surfaces of the cylinder, a generally isotropic radially extending acoustic emission symmetry about the catheter will be achieved. The lower frequency length mode resonance is favored by having electrodes disposed on the ends of the cylinder perpendicular to the central axis of the catheter, which allows greater penetration of the ultrasound energy and which may enhance gene transfection and liopfection (Ser. No. 09/223,231, now U.S. Pat. No. 6,372,498). The lower frequency cylindrical mode resonance and higher frequency thickness mode resonances may also be used. Conversely, circumferential electrodes (i.e.: electroded surfaces disposed on the curved inner and outer surfaces parallel to the central axis of the catheter), favor the higher frequency thickness mode resonance, which can generate relatively large amounts of thermal energy. The length and cylindrical excitation modes can also be used.
In both the case of rectangular bar and of cylindrical shaped transducers, a central longitudinally extending bore can be cut through the transducer, thereby providing access for a positioning wire therethrough. Alternatively, in the case of rectangular bar transducers, a lumen can be placed along one side of the bar to receive a guidewire without significantly affecting the resonant characteristics of the bar itself.
When using a plurality of either rectangular bar shaped or cylindrical transducers, the transducers will also radiate ultrasound energy in a direction along the axial length of the catheter. By spacing the transducers by a distance equal to (n+0.5)xcex, where n is an integral number, they can be set to interfere constructively with one another, thereby enhancing the effectiveness of the ultrasound delivery.
The present invention also provides systems for delivery of a uniform dose of therapeutic ultrasound energy comprising a thin polymer or copolymer film ultrasound transducer wrapped around a portion of the length of the outer surface of the catheter. As used herein, the phrase xe2x80x9ccopolymer film transducerxe2x80x9d shall include all polymer and copolymer films. An important advantage of such a copolymer film ultrasound transducer is that it delivers ultrasound in a radially outward direction along its length. As such, it is not necessary to either rotate or translate the catheter to deliver a uniform dose of ultrasound energy along the length of the body lumen.
Being isotropic, the ultrasonic emission from the copolymer film transducer is longitudinally uniform over the length of the copolymer transducer and is also uniform radially around the circumference of the transducer. Due to the polymeric nature of the transducer material, the transducer is itself advantageously flexible adding to the flexibility of the catheter system. Yet another important advantage of the wrapped copolymer film ultrasound transducer is its minimal thickness, making it ideally suitable for insertion into stents. When positioning stent struts against the vascular wall to reduce restenosis, over stretching of the vascular wall can result in a proliferative healing response. Therapeutic ultrasound following wall injury has been shown to substantially reduce and possibly eliminate the formation of obstructive neointimal hyperplasia.
By folding the thin copolymer film over upon itself prior to it being wrapped around the catheter, both the positive and the negative ends of the copolymer film can be disposed on opposite sides of the surface of the catheter system for attachment to electrodes such that a negative electrode contacts only the negative end of the copolymer film and a positive electrode contacts only the positive end of the copolymer film. Alternatively, the positive and negative ends of the copolymer film transducer can both be disposed inside the catheter body providing a smooth exterior surface with no edges which might snag on catheter delivery hardware or which might irritate patient tissues.
In yet another aspect of the present invention, combined ultrasound therapy and imaging systems are provided, both with and without enhanced drug delivery or gene transfection. In preferred aspects, one or more non-isotropic ultrasound transducers are used to direct ultrasound in one or more directions normal to the central axis of the catheter and thereby into the wall of the body lumen as described above. Rotation and translation of the catheter in the body lumen causes the imaging transducer to image the length and circumference of the body lumen concurrently with the one or more therapeutic ultrasound transducers delivering a uniform dose of therapeutic ultrasound along the body lumen.
The present invention also provides systems for controlled delivery of therapeutic agents into body lumens. Specifically, various balloon systems provide a protected and controlled release of a therapeutic agent along a region of the lumen while the present ultrasound transducer or transducers apply therapeutic ultrasound energy along the same region of the lumen into which the therapeutic agent has been released. The present balloon systems operate to seal off a portion of the lumen proximal the ultrasound transducer or transducers for release of a therapeutic agent therein. In addition, balloon systems are provided for selectively retrieving unused drug therapeutic agents after the therapeutic agents have been released into the lumen. Accordingly, after the therapeutic agent has been released to the blocked off portion of the lumen, unused amounts of the therapeutic agents can be easily retrieved.
In preferred aspects, a sheath is used to separate the balloon systems disposed at the exterior of the catheter system from the axially translating and/or rotating transducers disposed therein such that the transducers can be moved while the balloon system remains fixed in position, thereby blocking off the portion of the body lumen which is simultaneously treated by ultrasound energy and therapeutic agent delivery.
In summary, the present invention provides a variety of systems for delivering a uniform dose of therapeutic ultrasound energy along a body lumen. Systems accomplishing this result using one or more therapeutic transducers are set forth. Preferred transducer geometries for operating the transducers at resonance are also disclosed. Systems for axially translating and/or rotating the transducers at controlled velocities to deliver uniform ultrasound are set forth. Systems are provided using both isotropic and non-isotropic ultrasound transducers. Systems for operating successive axially spaced apart transducers in phase or 180 degrees out of phase to achieve either radial tissue compression displacement or axial tissue shear displacement, respectively, are also provided. Systems for blocking the ultrasound energy from certain surfaces of the ultrasound transducers so as to concentrate ultrasound energy in other preferred radial directions, thereby increasing the intensity of ultrasound delivery, are also disclosed.
Systems for delivering a uniform isotropic ultrasound dose without rotation or translation of the catheter using a thin copolymer ultrasound transducer wrapped around the length of a portion of the catheter are also set forth. Systems comprising imaging transducers used in conjunction with the preferred therapeutic transducers are also set forth. Balloon systems for controlled delivery and removal of therapeutic agents are also set forth.